Balloon angioplasty and stenting (percutaneous coronary interventions with or without the use of stents) are widely used procedures for coronary artery disease. Unfortunately, renarrowing (restenosis) of the dilated artery occurs in 25-40% of patients within six months after these procedures, which requires repeat angioplasty or bypass surgery (Dangas and Kuepper, 2002; Michaels and Chatterjee, 2002). Therefore, restenosis represents a major problem limiting the long-term efficacy of these revascularization therapies. Moreover, following coronary artery bypass surgery, narrowing (stenosis) of the transplanted artery can also occur that necessitates further medical treatments.
Abnormal migration and proliferation of VSMCs are critical events in the pathogenesis of artery obstructive diseases such as restenosis (Bailey, 2002; Levitzki, 2005; Sanz-Gonzalez et al., 2004). While several growth factors and cytokines are involved in the development of restenosis, many lines of evidence have indicated that PDGF plays a prominent role in the pathogenesis of restenosis. PDGF is the most potent mitogen and motogen for VSMCs (Heldin and Westermark, 1999). PDGF is present at sites of vascular injury from activated platelets, monocytes, and cells of the artery wall (Raines, 2004). Expression of exogenous PDGF in animal arteries can induce intimal thickening through stimulation of VSMC proliferation and migration and synthesis of extracellular matrix (Pompili et al., 1995). Importantly, inhibition of PDGF as well as PDGFR by immunological, molecular biological, and pharmacological methods can suppress development of restenotic lesions in animal models (Ferns et al., 1991; Levitzki, 2005; Myllarniemi et al., 1999; Sirois et al., 1997).
Imatinib (Gleevec, STI571, CGP57148B) is the first protein tyrosine kinase inhibitor that has been successfully developed into a targeted therapy drug. It is currently used to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumor based on inhibition of Bcr-Abl and c-Kit protein tyrosine kinases, respectively (Deininger et al., 2005; Logrono et al., 2004). Besides Bcr-Abl and c-Kit, imatinib also inhibits PDGFR tyrosine kinase (Buchdunger et al., 1996; Druker et al., 1996). Experiments in animals have shown that imatinib inhibits restenosis after balloon angioplasty and stenosis after allograft (Myllarniemi et al., 1999; Sihvola et al., 2003). Inhibition of PDGFR by imatinib, however, requires micromolar concentrations in cell-based assays (Buchdunger et al., 1996; Sanz-Gonzalez et al., 2004).
An additional approach to reducing restenosis is through the use of stents. A stent is a wire mesh tube used to prop open an artery after angioplasty. Restenosis is found to be less common in stented arteries.